Integrating Genomics into Drug Discovery and Development: Challenges and Aspirations
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REVIEW ARTICLE
Integrating Genomics into Drug Discovery and Development: Challenges and Aspirations Rajiv Raja1 • Young S. Lee1 • Katie Streicher1 • James Conway1 • Song Wu1 Sriram Sridhar1 • Mike Kuziora1 • Hao Liu1 • Brandon W. Higgs1 • Philip Z. Brohawn1 • Carlos Bais1 • Bahija Jallal1 • Koustubh Ranade1
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Ó Springer International Publishing AG 2017
Abstract Molecular biomarkers are increasingly being used to identify subgroups of patients that have a higher chance of benefiting from targeted therapies. Identification of predictive biomarkers and development of companion diagnostics to accompany targeted agents have been shown to significantly improve the efficacy and approval rate of these novel therapies, making treatment decisions more personalized to individual patients. Mutations of epidermal growth factor receptor (EGFR) and rearrangements of anaplastic lymphoma kinase (ALK) in non-small-cell lung cancer and of BRAF in melanoma provide great examples of driver mutations defining patient subgroups that respond to specific therapeutic agents. Recent advances in genomic technologies such as next-generation sequencing offer new opportunities for discovery and development of targeted therapies. They also pose numerous challenges in implementing molecularly guided precision medicine in clinical care. In this article, we review how molecular diagnostics have evolved over recent decades, discuss types and capabilities of clinically applicable genomic technologies, and highlight examples of companion diagnostics that have gained regulatory approval. Finally, we discuss technical and regulatory challenges associated with incorporating next-generation genomic technologies into clinical practice and consider potential ways to overcome these challenges to enable precision medicine.
& Rajiv Raja [email protected] 1
MedImmune, LLC., 1 Medimmune Way, Gaithersburg, MD 20878, USA
Key Points Molecular biomarkers are highly valuable in the identification of patient subgroups that benefit from targeted therapies. Recent advances in genomic technologies enable highly multiplexed biomarker analysis for comprehensive disease profiling. As challenges related to complex, highly multiplexed technologies are addressed, these new genomic technologies will enable disease-based diagnostic panels that will revolutionize personalized medicine.
1 Introduction Historically, drug development and clinical practice have focused on the general characteristics of a disease rather than accounting for individual variability. This type of drug development strategy that targets an entire disease population assumes that the patient population is quite homogenous in pathology and etiology. Accordingly, this strategy has led to disappointing outcomes in numerous clinical trials in diseases with a high degree of patient heterogeneity. It is now widely accepted that a one-sizefits-all approach for drug development is extremely costly and inefficient (reaching 2558 million USD after adjusting for failures [1]) while also leading to suboptimal tr
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